Process for preparing methylvanillyl ketone from isoeugenol

ABSTRACT

Methylvanillyl ketone is prepared from a &#34;through process&#34; involving oxidation of isoeugenol followed by subsequent acidic hydrolysis.

BACKGROUND

This invention relates to a new, alternate process for preparingmethylvanillyl ketone (MVK), or 4-hydroxy-3-methoxyphenylacetone, whichis a useful intermediate for the synthesis of methyldopa, one of themost important antihypertensive agents.

The use of MVK in the methyldopa process has been disclosed in U.S. Pat.No. 2,868,818 which comprises the addition of a cyanide anion to MVK toform 4-methyl-4-(4-hydroxy-3-methoxybenzyl)hydantoin followed by basichydrolysis to form α-methyl-β-(4-hydroxy-3-methoxyphenyl)alanine.Subsequent acidic hydrolysis produces methyldopa, i.e.,α-methyl-β-(3,4-dihydroxyphenyl)alanine.

Presently, MVK is manufactured from vanillin and nitroethane [Kulka etal, J. Am. Chem. Soc., 65, 1184 (1943)]. However, this process suffersfrom the high cost of vanillin and the fact that there is only onesupplier for nitroethane.

For these reasons, an alternate process for the production of MVK isdesirable to safeguard the continuous production of methyldopa.

The novel process of the present invention concerns the direct oxidationof unprotected isoeugenol to form a glycol intermediate followed bysubsequent acidic conversion to MVK. Although the process includes twochemical reactions, it is virtually a single-step "through process". MVKis the first and only isolated product.

The peroxide-oxidation of a protected isoeugenol, i.e., acetylisoeugenol, to form an epoxide precursor of MVK is known (K. Freudenberget al, Chem. Ber., 76, pp. 1005-1006, 1943). However, Freudenberg etal's process is not a "through process". It involves three steps, all ofwhich require the isolation of products. It also suffers from low yield(30%).

Moreover, the novel process of this invention is distinguishable fromFreudenberg et al's process. First, as will be shown later in EquationA, the present process oxidizes unprotected isoeugenol to generate aglycol intermediate instead of an epoxide. Second, the glycolintermediate generated does not come from the hydrolysis of a precedingepoxide. The epoxide simply does not exist due to the presence of a freephenol group in isoeugenol.

Therefore, it is an object of the present invention to provide a new,alternate process for the production of methylvanillyl ketone fromisoeugenol.

It is also an object of this invention to provide a process which iseconomically more advantageous than the current vanillin process for themanufacturing of MVK.

Still another object of this invention is to provide a "through process"for preparing MVK which requires no isolation of products before that ofMVK and thus is simpler, shorter, and more efficient than Freudenberg etal's synthesis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns a new, alternate process for theproduction of methylvanillyl ketone (MVK). The process can berepresented as follows. ##STR1## wherein R is hydrogen, C₁₋₅ alkylespecially methyl, ethyl, propyl, butyl or amyl, trifluoromethyl ortrichloromethyl; and the oxidation reagent is peroxide such as hydrogenperoxide or disuccinoyl peroxide, peracid such as performic acid,peracetic acid, peroxytrifluoroacetic acid, monopersuccinic acid,m-chloroperbenzoic acid, p-methoxycarbonylperbenzoic acid,O-sulfoperbenzoic acid or monoperphthalic acid, or other oxidationreagents such as iodine-silver oxide, iodine-mercuric oxide,N-bromosuccinimide-perchloric acid, or thallium triacetate.

The oxidation is usually conducted in an aqueous solution of an organicacid such as formic, acetic, propionic, trichloroacetic, or trifluoroacetic acid. The formic acid and acetic acid generally give betterresults. The preferred oxidation reagents are hydrogen peroxide andperacetic acid. The most preferred embodiment is the combination ofhydrogen peroxide and formic acid. The oxidation generally requires mildheating at about 25° C.-100° C., preferably at 30° C.-60° C., for about1-6 hours or until the reaction is substantially complete. If hydrogenperoxide and formic acid are used at 35° C.-40° C., the reaction issubstantially complete in about 2.5 hours or less.

The in situ conversion of the resulting glycol monoester withoutisolation to MVK is accomplished by heating the reaction mixturetogether with an aqueous solution of a strong acid and an inert solventsuch as benzene, toluene or xylene. The strong acid used is usuallysulfuric, alkyl or aryl sulfonic, hydrobromic, hydrochloric orphosphoric acid.

Preferably, a sufficient amount of 10%-20% aqueous sulfuric acid andtolune is added to the reaction mixture and the entire mixture is heatedto reflux until the reaction is substantially completed. Under thepreferred conditions, the reaction time ranges from 6-16 hours.

Another embodiment of the present invention is a novel improvement ofthe Freudenberg et al process which involves the oxidation of acetylisoeugenol with perbenzoic acid in chloroform followed by acid treatmentto give a 30% yield of MVK. The improved process, however, usesperacetic acid or other oxidation reagents in an acidic medium such asan alkanoic acid for the initial oxidation. This modification eliminatesall the isolations of intermediates required by Freudenberg et al. As aresult, the over-all yield of MVK unexpectedly increases fromFreudenberg et al's 30% to 85%. The improved process can be representedas follows: ##STR2## wherein R and the oxidation reagent are aspreviously described.

The improved method is also a single-step "through process". Afterisoeugenol is protected by alkanoylation such as acetylation in aceticanhydride and sodium acetate or butanoylation with butynylchloride, thereaction mixture is diluted with an inert solvent such as toluene,xylene or benzene and treated directly with peracetic acid or otheroxidation reagents as previously described. Following mild heating atabout 25° C.-100° C., preferably about 50° C.-60° C. for about 1-6hours, the substantially complete reaction is quenched with aqueoussodium sulfite to destroy excess oxidation reagent. When peracetic acidis used, the oxidation is essentially complete within 2-3 hours. Theresulting alkanoyl isoeugenol epoxide is converted in situ to MVK uponheating with a strong acid in an inert solvent as described previouslyin Equation A.

It is essential to eliminate any isolation of intermediates before thelast step. As illustrated by Examples 2 and 3, the yield for the"through process" is 85% (Example 2) while the yield from stepwiseprocess (Example 3) drops to 54%.

EXAMPLE 1 Methylvanillyl Ketone (MVK) from Isoeugenol

A solution of 30% aqueous hydrogen peroxide (9 ml, 85.5 mm) and formicacid (16 ml, 88%) is added to a solution of isoeugenol (8.1 gm, 50 mm)in formic acid (4 ml). The reaction mixture is stirred at 35° C.-40° C.under nitrogen atmosphere for 3 hours. The resulting1-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol-monoformate is treatedwith 10% aqueous sulfuric acid (125 ml.) and toluene (125 ml.). Afterrefluxing with mixing for 6 hours, the reaction mixture is cooled toroom temperature, and the toluene layer separated. The aqueous layer isextracted with fresh toluene and the toluene layers are combined, washedwith saturated aqueous sodium sulfate, dried over anhydrous sodiumsulfate and concentrated to give methylvanillyl ketone in 48% yield.

EXAMPLE 2 Methylvanillyl Ketone from Acetyl Isoeugenol (Through Process)

A mixture of isoeugenol (8.21 g., 50 mm.), acetic anhydride (5.62 g., 55mm.) and anhydrous sodium acetate (0.41 g., 5 mm.) is heated at 100°C.-105° C. under nitrogen atmosphere for 2.5 hours. The reaction mixtureis cooled and diluted with 65 ml. of toluene before a solution (11 ml.)of 38.6% peracetic and 0.85 g. of sodium acetate in acetic acid is addedslowly. After heating at 50° C.-60° C. for 2-3 hours, the reactionmixture is cooled to 20° C. and treated with aqueous sodium bisulfite(2.8 g.) to destroy excess peracetic acid. The entire mixture is mixedwith 8 ml. of toluene, 50 ml. of 14% aqueous sulfuric acid, and isheated with stirring to reflux for 12.5 hours. After cooling to ambienttemperature, the toluene layer is separated, and the aqueous layerextracted 3×20 ml. of toluene. The toluene layers are combined, washedwith saturated aqueous sodium sulfate, dried over anhydrous magnesiumsulfate and concentrated in vacuo to give methylvanillyl ketone in 85.3%yield.

EXAMPLE 3 Methylvanillyl Ketone from Acetyl Isoeugenol (StepwiseProcess) Step (a): Preparation of Acetyl Isoeugenol

To a solution of isoeugenol (344 g., 2.1 moles) in 420 ml. of pyridineunder nitrogen atmosphere is added 428 ml. of acetic anhydride over aperiod of 30 minutes. The resulting solution is stirred at roomtemperature overnight followed by treatment with ice-water (1400 ml.).After stirring for three hours, the resulting precipitate is filtered,washed with water (3×500 ml.) and dried in vacuo to give 381.7 g. ofcrude product. Acetyl isoeugenol (269 g., 62%) is obtained from washingthe crude product with n-hexane.

Step (b): Preparation of Acetyl Isoeugenol Epoxide

To a solution of acetyl isoeugenol in 65 ml. of toluene under nitrogenatmosphere is added a solution of 38.6% peracetic acid (11 ml.) followedby addition of 0.85 g. of sodium acetate. The reaction mixture isstirred and heated at 50° C.-62° C. for 2.5 hours before it is cooledand quenched with aqueous sodium bisulfite (2.89 g. in 8 ml. of coldwater). The crude product so obtained is directly used in the next step.

Step (c): Preparation of Methylvanillyl Ketone

To the crude product from step (b) is added 10% aqueous sulfuric acid(50 ml.). The reaction mixture is stirred and heated at reflux for 12.5hours. After cooling to room temperature, the toluene layer is separatedand the aqueous layer is extracted with 3×20 ml. toluene. The combinedtoluene layers are dried over magnesium sulfate, filtered, andevaporated in vacuo to give methylvanillyl ketone in 54% over-all yieldbased on isoeugenol.

What is claimed is:
 1. A process for preparing methylvanillyl ketone ina single step, through process comprising:oxidizing isoeugenol with anoxidation reagent selected from the group consisting of peroxides,peracids, iodine-silver oxide, iodine-mercuric oxide,N-bromosuccinimide-perchloric acid or thallium triacetate in an aqueoussolution of an organic acid selected from the group consisting of C₁₋₅alkanoic acid, trifluoroacetic acid and trichloroacetic acid at atemperature of about 25°-100° C. to form a glycol monoester; andconverting in situ the resulting glycol monoester by refluxing with astrong acid selected from the group consisting of sulfuric acid, alkylor aryl sulfonic acid, hydrochloric acid, hydrobromic acid, andphosphoric acid in an inert solvent to obtain said methylvanillyl ketonetherefrom without isolation of any intermediates.
 2. The process ofclaim 1 wherein the oxidation reagent is peroxide or peracid.
 3. Theprocess of claim 1 wherein the oxidation reagent is hydrogen peroxide orperacetic acid.
 4. The process of claim 1 wherein the strong acid is10%-20% aqueous sulfuric acid.
 5. The process of claim 1 wherein theperoxide is hydrogen peroxide; the strong acid is 10%-14% aqueoussulfuric acid; and the inert solvent is toluene.